In the United States alone, post-traumatic stress disorder (PTSD) has a lifetime prevalence of 7-12%. Treatments for the disorder are of some success, yet novel approaches to therapy remain urgently needed. We have been investigating an interesting aspect of anesthetic-induced amnesia in which we discovered that very low doses of selected anesthetic agents given at the time of learning are capable of blocking the mnemonic boost associated with emotionally arousing material. This indicates that the emotional burden and pain of a traumatic event is dissociable from the memory of the event itself and that the debilitating aspects of a traumatic experience should be mitigated by the properly timed use of low-dose anesthetic therapy. We suspect this effect of anesthesia might have great clinical utility for treating PTSD. However, before starting a clinical trial in PTSD patients, it remains to be determined exactly which anesthetic agents will offer the greatest therapeutic potential, what doses should be used, and whether or not post-learning administration of selected agents might suppress emotional memory by interfering with re-consolidation. Thus, the overall goal of this exploratory work is to begin to establish which anesthetics produce the most useful emotional memory blocking effects. Experiments will be conducted in volunteers exposed to various subanesthetic doses of select anesthetics in order to identify the neural correlates of low-dose anesthetic action with reference to the following specific aims. Specific aim 1: We aim to elucidate the differential effects of selected anesthetic agents on human emotional memory and determine the doses needed to block emotional memory with a few selected agents. Prior studies suggest that ketamine, propofol, dexmedetomidine and nitrous oxide might each have the potential to block emotional memory at low subanesthetic doses. Specific aim 2: We aim to identify the neural correlates of anesthetic drug by emotional memory interactions. Using event-related functional magnetic resonance imaging (fMRI) techniques and with reference to an amygdala-specific hypothesis we will determine whether those agents that block human emotional memory do so through a site-specific amygdala effect. Together these studies will provide a critically needed fundamental basis for developing a rational proposal to treat PTSD using the novel therapy of anesthetic-induced blockade of emotional memory functioning. PUBLIC HEALTH RELEVANCE: A recent study by Tanielian and Jaycox (Editors for a RAND corporation report) states, "that total PTSD and major depression-related costs incurred for 1.6 million troops within the first two years after returning home could range from $4.0 billion to $6.2 billion". Should the innovative approach proposed herein to treat PTSD be half as effective as is hoped, then these costs should be dramatically reduced or eliminated and numerous lives currently at-risk might be saved.